The paradox of the genetics underlying infertility is that infertile individuals must have descended from fertile parents. Nonetheless, previous studies have attributed infertility in part to inherited genetic factors. As is the case with many pervasive human health conditions, this results from combinatorial effects of multiple genes, environmental factors and their interactions. Such small effects and interactions are often difficult to detect in both human populations and mouse models. The proposed research will identify genetic variation underlying male infertility using a new mouse population called the Collaborative Cross (CC). The CC is designed to facilitate mapping genes associated with complex traits. During the breeding process, up to 50% of incipient lines stop producing offspring and are declared extinct, and male infertility is a major mechanism of this extinction. This large and diverse population of infertile male mice can be used to better understand the biology and genetics of male infertility and its associated reproductive parameters such as sperm count and testis structure. This project is also valuable to develop new methods that apply to the CC population.